High Concentration Baclofen Preparations

ABSTRACT

Stable aqueous solutions comprising concentrations of baclofen in the range of greater than 2.0 mg/mL up to about 10 mg/mL are disclosed. These solutions can be used as pharmaceuticals for parenteral or oral administration. The invention also provides methods of preparing said stable aqueous baclofen solutions.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. Ser. No. 11/156,370,filed Jun. 17, 2005, which claims benefit of U.S. ProvisionalApplication No. 60/587,274, filed Jul. 12, 2004.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to aqueous solutions comprising highconcentrations of baclofen in the range of greater than 2.0 mg/mL up toabout 10 mg/mL. These solutions can be used as pharmaceuticals. Theinvention also relates to various methods of preparing stable solutionsin this concentration range.

2. Background

Baclofen is a skeletal muscle relaxant and antispastic agent. Baclofenis a structural analog of the inhibitory neurotransmittergamma-aminobutyric acid (GABA), and may exert its effects by stimulationof the GABA_(B) receptor subtype. Baclofen is the generic (USAN) name(USP Dictionary of USAN and International Drug Names 2003) for4-amino-3-(p-chlorophenyl) butyric acid, a derivative of λ-aminobutyricacid. Its structural formula is:

Baclofen is a white to off-white, odorless or practically odorlesscrystalline powder, with a molecular weight of 213.66. It is slightlysoluble in water, very slightly soluble in methanol, and insoluble inchloroform. Its slight solubility in water makes it difficult to obtainstable aqueous solutions of baclofen that have concentrations greaterthan approximately 2 mg/mL.

Baclofen can be administered orally, but when injected directly into theintrathecal space of a patient effective CSF concentrations are achievedwith resultant plasma concentrations 100 times less than those occurringwith oral administration. Baclofen injections (Lioresal Intrathecal,Medtronic) are therefore commonly administered intathecally via animplanted pump to manage severe spasticity of spinal cord origin.(McEvoy, 2003) Presently, baclofen is commercially available forinjection as a 2 mg/mL solution having a pH of 5 to 7 and the followingsimple preservative-free formula (Lioresal Intrathecal package insert):

Baclofen 2 mg Sodium chloride 9 mg Water for injection qs 1 mL

Unfortunately, the 2 mg/mL concentration has been inadequate to controlthe pain and symptoms of some patients. An additional difficulty is thatmixing a 2 mg/mL baclofen injection with other drugs such as morphine orhydromorphone in “cocktails” to aid in control of pain can dilute thebaclofen content to unacceptably low levels. In these and otherapplications, it can be desirable to administer a more concentratedsolution of baclofen in order to reduce the volume of baclofen solutionto be administered. But due to baclofen's slight solubility in water,aqueous solutions having a higher concentration of baclofen have notbeen shown to be commercially viable products. At higher concentrationsbaclofen may not entirely dissolve in aqueous solution, or it may havean unacceptable tendency to precipitate out of solution during storage.

An upper limit on room temperature aqueous solubility of baclofen hasbeen reported by some sources as 4.3 mg/mL (Ahuja, 1985), however thatconcentration was achieved by allowing the baclofen to dissolve over aperiod of weeks or months until it reached an equilibrium state. In anequilibrium solution there is always particulate baclofen present. Thesolution is at equilibrium because the rate at which the baclofenparticulates dissolve is equal to the rate at which the dissolvedbaclofen precipitates out of solution.

Baclofen has not been shown to be nearly as soluble when lesstime-consuming methods are used to dissolve it, nor has it been reportedthat concentrations equaling or even approaching the 4.3 mg/mLconcentration can be achieved in solutions that are not at equilibrium,i.e. where no particulate baclofen is present. Commercially andpharmaceutically acceptable baclofen solutions must not contain anysignificant amount of particulates, and the baclofen must stay insolution without precipitating prior to and during administration to apatient. Only solutions of baclofen having a concentration of 2 mg/mLhave previously been demonstrated to have the properties that make theman acceptable commercial pharmaceutical product by remaining stable forextended periods of time without precipitation of significant amounts ofbaclofen particulates.

Various sources have reported stable suspensions or syrups of baclofenfor oral administration that had concentrations even higher thanequilibrium concentration of 4.3 mg/mL, (Allen et al., 1996; Johnson andHart, 1993) but none of these preparations are acceptable forpharmaceutical injection uses. Other sources have reported theproduction of microspheres containing 12 to 50% baclofen (Cruaud et al.,1999, but such microspheres are not compatible with delivery systemsrequiring an aqueous solution of baclofen.

It was also known that baclofen can be readily dissolved in very highand very low pH solutions. For example, Ahuja (1985) reported thatconcentrations of baclofen greater than 20 mg/ml could be obtained bydissolving baclofen in aqueous solutions of 0.1N HCl or aqueoussolutions of 0.1N NaOH. Significantly, the pKa₁ for baclofen at 20° C.is reported by Ahuja to be 3.87±0.1 and the pKa₂ at 20° C. 9.62±0.1. ThepH of a 0.1N HCl solution is well below the pKa₁ value for baclofen andthe pH of a 0.1N NaOH solution is well above the pKa₂ value forbaclofen. Thus baclofen at these pHs would be expected to have differentsolubility properties than baclofen dissolved in more neutral pHsolutions. Moreover, it would be expected that high concentrationsolutions of baclofen that were prepared at pHs below pKa₁ or above thepKa₂ value of baclofen would tend to fall out of solution when the pH ofthe solution was adjusted to a value between the pKa₁ and pKa₂ values.Because solutions having a pH of less than 4 or greater than 8.5 wouldnot expected to be acceptable pharmaceutically, the use of very high orvery low pH solutions of baclofen does not resolve the need for higherconcentration aqueous solutions of baclofen.

Therefore, there appears to be a clinical need for more concentratedaqueous solutions of baclofen having acceptable pharmaceuticalproperties, and most preferably for concentrated solutions that are alsostable in a variety of storage conditions and for extended periods oftime.

BRIEF SUMMARY OF THE INVENTION

The present invention provides high-concentration, aqueous solutions ofbaclofen, including solutions that are stable under a variety of storageconditions and for extended periods of time. The present invention alsoprovides methods for preparing such compositions.

DETAILED DESCRIPTION OF THE INVENTION

Preferred embodiments include stable, high-concentration baclofensolutions suitable for therapeutic use and methods of preparing suchsolutions. Other preferred embodiments provide methods for enhancing oraccelerating the solubilization of baclofen solutions.

Commercially available lower-concentration baclofen solutions arecurrently approved only for oral or intrathecal administration.Therefore, in preferred embodiments, the present invention provides highconcentration baclofen solutions suitable for oral or intrathecaladministration. Forms of neuraxial administration other than intrathecaladministration are also preferred, such as epidural administration. Inalternative embodiments, baclofen solutions of the present invention canbe used for any other clinically suitable type of administrationincluding, but not limited to, intravenous, intramuscular orsubcutaneous injection.

As discussed above, current commercial preparations of baclofen consistof baclofen, sodium chloride and water. The solutions do not require anyspecial preservation components such as antioxidants or buffers due tobaclofen's high degree of chemical stability. It has been calculatedthat in aqueous solution at room temperature and neutral pH (pH 6 to 7)it will take 10 years before there is 10% decomposition of the dissolvedbaclofen. (Ahuja, 1985.) Antimicrobial preservatives are undesirable forintrathecal and epidural injections. Thus, preservatives areunnecessary.

Instead, it is the physical stability of baclofen that produces the mostdifficulties in a therapeutic context. Baclofen dissolves poorly inwater. Once dissolved, at higher concentrations baclofen tends toprecipitate out of solution after a relatively short period of time,lowering the concentration of baclofen in solution and producingundesirable particulate matter. For therapeutic reasons, any solution ofbaclofen intended for pharmaceutical use should meet the particulatematter requirements of the USP, 2004. Thus solutions that are likely toproduce particulates during normal storage are not pharmaceuticallyacceptable.

Generally, baclofen solutions are obtained for pharmaceutical use eitherby a drug-supplier which prepares and ships the solutions to the enduser or their medical care provider or pharmacist, or the solutions areprepared shortly prior to use by a medical care provider or pharmacist.Solutions that are to be used for intrathecal injection by an implantedpump must generally be stable at body temperature (37° C.) for at leastabout 30 days. Otherwise the baclofen solution may form unacceptableprecipitates or microparticulates while in the patient's implanted pump.Therefore, the long-term stability of the baclofen solution is criticalwhen the solution is used in these applications (e.g. stability at 37°C. of at least 30 days for solutions prepared immediately prior toinjection is usually required).

Stability for longer time periods is also an issue where the drug isprovided by a drug supplier that mixes the drug and ships it to the enduser or their medical care provider or pharmacist. In such cases thedrug may be stored, usually at room temperature or under refrigeration,for several weeks, months, or even years prior to administration. Again,it is highly desirable that the drug not formpharmaceutically-unacceptable precipitates or microparticulates eitherduring storage prior to administration or while residing in theimplanted pump prior to injection into the intrathecal space.

The inventors attempted to prepare aqueous baclofen solutions atconcentrations of 3 mg/mL, 4 mg/mL, and 5 mg/mL by direct dissolution in0.9% sodium chloride injection, USP (normal saline). The normal salinewas commercially procured by the inventors and was at ambient roomtemperature (about 23° C.) for use in the testing. Appropriate amountsof authentic baclofen powder were weighed and added to the normal salineand shaken to aid in dissolution. Even vigorous shaking for 60 minutesdid not result in complete dissolution or a clear solution at the4-mg/mL and 5-mg/mL concentrations. Both the 4-mg/mL and especially the5-mg/mL concentration retained large amounts of undissolved powder. Thesolutions were further subjected to automated shaking for one week atroom temperature which still failed to result in complete dissolution.The solutions were visibly unacceptable for use as an injection. HPLCanalysis of the solutions after filtration through a 0.22-micron filterto remove the undissolved powder found that the amount of baclofenactually dissolved in the normal saline in both the putative 4 mg/mL and5 mg/mL samples was about 3.3 to 3.5 mg/mL. The inventors believe thatthis the concentration represents the “practical solubility” ofbaclofen. In practice, it is common to find that a drug's “practicalsolubility” is somewhat below the maximum solubility that is reported,therefore this result is unsurprising.

As used herein, the “practical solubility” is the concentration ofbaclofen that can be dissolved using simple practical dissolution stepssuch as adding the powder to an aqueous solvent and then shaking orstirring the solvent by hand or with a mechanical device. Whenattempting to prepare solutions having concentrations higher than thepractical solubility concentration, it is common to observe residualundissolved matter, precipitation of microparticulates, or both.

Baclofen's low degree of practical solubility is likely to be the mainreason that stable solutions of Baclofen are only available commerciallyat a concentration of 2 mg/mL. As used herein a “stable solution” meansa solution containing dissolved baclofen, wherein nopharmaceutically-unacceptable quantity of undissolved baclofen ispresent in contact with the solution and wherein the dissolved baclofendoes not precipitate out of solution to a pharmaceutically unacceptabledegree for a period of at least 1 week when the solution is stored atroom temperature. Typically, solutions that are stable under normalstorage conditions for periods of many months or more preferably forperiods of one or more years are most suitable for use as pre-preparedsolutions that can be commercially supplied to end users, medical careproviders or pharmacists. However, even though a solution may not besuitable for long-term storage or commercial distribution aspre-prepared solutions, solutions that are stable under normal usageconditions (i.e. for periods of at least many days or weeks, andpreferably for periods of at least 30 days) can be used in applicationswhere the solution is prepared a suitable period of time prior toadministration.

Stable aqueous solutions with concentrations of baclofen higher thanabout 3.5 mg/mL appear not to be readily achievable by directdissolution, as observed above. Stable aqueous solutions withconcentrations of baclofen higher than about 4.3 mg/mL appeared to beimpossible based upon previous observations of the upper limit ofbaclofen's aqueous solubility at room temperature.

As used herein “aqueous solution” means a solution that is at least 80%water by weight, preferably at least 90% water by weight, morepreferably at least 95% water by weight and most preferably at least 98%water by weight. In certain embodiments, aqueous solutions of thepresent invention include solutions containing appropriate bufferingagents, salts, preservatives, other pharmaceutically acceptableadditives or any combination thereof. Alternately, aqueous solutions ofthe present invention can contain no such additives and can consistsolely of baclofen and water. In preferred embodiments the aqueoussolution of the present invention is a normal saline solution ofbaclofen without any further additives.

Generally, the present invention provides stable aqueous baclofensolutions at concentrations higher than the 2.0 mg/mL concentration thatis currently commercially available, and methods of preparing suchsolutions. In particular, the present invention provides stable aqueousbaclofen solutions having concentrations greater than about 2.1, 2.2,2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6,3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0,5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9 and 6.0 mg/mL. The presentinvention provides stable aqueous baclofen solutions havingconcentrations less than about 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5,8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5 or 12.0 mg/mL.

Any appropriate form of baclofen can be used to prepare the solutions ofthe present invention. In preferred embodiments, appropriate forms ofbaclofen include baclofen solids such as powdered, lyophilized ormicrofluidized baclofen. In other embodiments, the baclofen can beprovided as an aqueous or non-aqueous solutions of baclofen, includingbuffered solutions, wherein any pharmaceutically undesirable componentof said solution is either diluted to pharmaceutically-acceptable levelsor removed from the final baclofen solution prior to pharmaceuticaladministration.

Because baclofen is stable when heated and is not subject to rapidhydrolysis, the present inventors first used a combination of heat andintense agitation to see if the solubility of baclofen at its normalneutral pH could be increased. Although it seemed counter-intuitivebased on the published reports of baclofen aqueous solubility at 4.3mg/mL in an authoritative source (Abuja, 1985), the inventors attemptedto use heat and intense agitation to achieve baclofen concentrations innormal saline of 4, 5, 6, 8, and 10 mg/mL.

The inventors observed that baclofen solutions having concentrations inthe range of about 3 to about 8 mg/mL can be obtained by mixing theappropriate quantity of baclofen with an aqueous diluent and heating thesolution to a temperature of at least about 30° C., at least about 40°C., at least about 50° C., preferably at least about 60° C., and mostpreferably at least about 70° C. and a temperature of less than about90° C., less than about 95° C., less than about 100° C., less than about121° C., or most preferably less than the temperature at which baclofenthermal degrades to a significant degree. The heat is applied whilesimultaneously subjecting the solution to intense agitation, e.g.sonication, high-speed stirring, etc. The temperature range of at leastabout 60° C. to at less than about 100° C. is most preferred. Further,it is generally preferable, although not required, that the aqueoussolution be heated to a temperature lower than it's boiling point toprevent significant evaporation of the aqueous solvent duringdissolution. Dissolution temperatures of 100° C. or higher that do notboil off the aqueous solvent can be obtained by means known to those ofskill in the art, such as by increasing the atmospheric pressure thatthe solution is subjected to during heating. One common means ofachieving this result is by autoclaving the solution.

Surprisingly, the solutions obtained through the use of heat andintensely agitation described above have enhanced physical and chemicalstability characteristics. The solutions are stable for periods of atleast 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25 or 26 weeks, for periods of at least 7, 8, 9, 10or 11 months, or for periods of at least 1, 1½, 2, 2½ or 3 years,depending on the concentration of baclofen in solution and the storageconditions used.

In another embodiment of the invention, stable baclofen solutions can beproduced by acidification and back titration. Baclofen solutions havingconcentrations up to about 10.0 mg/mL can be prepared by dissolvingbaclofen in an acidic solution, preferably one having a pH lower thanthe pKa₁ of baclofen. For example, pH values lower than about 3.87,lower than about 3.0, lower than about 2.0, lower than about 1.5, oreven lower than a pH of about 1.0 can be used advantageously.Surprisingly, once the baclofen has been dissolved in the acidicsolution, and prior to pharmaceutical administration, the baclofensolution can be back titrated to a pH of 4.0 to 8.5 withoutprecipitation of baclofen particulates. The titration is carried out byadding a base to the acidic solution until the pH is adjusted to a pH inthe desired range. A final pH of 5.0 to 7.0 is currently preferred forbaclofen solutions intended for pharmaceutical uses such as intrathecalinjection, but pH ranges of 4.5 to 8.0 and of 4.0 to 8.5 can also besuitable for such uses. These pH ranges are intended to be illustrativeof appropriate values for uses such as intrathecal injection. Theappropriate pH ranges for any particular pharmaceutical application willbe readily apparent to those skilled in the art, and the final pH of thebaclofen solution can be any pharmaceutically acceptable pH appropriatefor a given use. In addition, baclofen solutions prepared by this methodcan be stored at a pH that is not appropriate for a given pharmaceuticaluse so long as the solution is titrated to a pharmaceutically acceptablepH prior to administration.

In preferred embodiments, the acid or acids used to produce the acidicsolution are pharmaceutically acceptable acids such as hydrochloricacid, sulfuric, phosphoric, acetic, tartaric, fumaric acid and the like.

In other embodiments, the acidic solution is further subjected to heat(as described above) intense agitation (as described above) or both tospeed or enhance the dissolution of the baclofen or to improve thestability of the aqueous baclofen solution being prepared.

Alternately, stable baclofen solutions can be produced by alkalinizationand back titration. That is, solutions having concentrations of baclofenof about 10.0 mg/mL or lower can be prepared by dissolving baclofen in abasic solution, preferably one having a pH higher than the pKa₂ ofbaclofen. For example, solutions of pH higher than about 9.62, higherthan about 10.0, higher than about 11.0, higher than about 12.0, andeven higher than the pH of about 13.0 can be used advantageously. Oncethe baclofen is dissolved in the basic solution the pH can be backtitrated to a pH of about 4.0 to 8.5, or preferably can be titrated to apH of 5.0 to 7.0, or to other pH values appropriate for pharmaceuticaluses such as intrathecal injection, as discussed above. For use in otherapplications, pharmaceutical or otherwise, or during storage prior touse the baclofen solution can be titrated to a lower pH or can bemaintained for some period of time at the original basic pH.

In preferred embodiments, the base or bases used to produce the basicsolution are pharmaceutically acceptable bases such as sodium hydroxide,potassium hydroxide and the like.

In other embodiments, the basic solution is further subjected to heat(as described above) intense agitation (as described above) or both tospeed or enhance the dissolution of the baclofen or to improve thestability of the aqueous baclofen solution being prepared.

Surprisingly, the solutions obtained by dissolution of baclofen inacidic or basic solutions also have enhanced physical and chemicalstability characteristics both before and after back titration to a moreneutral pH. The solutions are stable for periods of at least 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25 or 26 weeks, for periods of at least 7, 8, 9, 10 or 11 months, orfor periods of at least 1, 1½, 2, 2½ or 3 years, depending on theconcentration of baclofen in solution and the storage conditions used.

It alternate embodiments, the acidic or basic solution of baclofen canbe lyophilized to form a powder that is reconstituted and back titratedprior to use. Such embodiments would be especially useful for preparingsolutions having very high concentrations of baclofen, e.g. 6.0 mg/mL orhigher, that are stable for a period of time that is pharmaceuticallyacceptable for a given use, but that is not acceptable for a solutionthat is commercially distributed as a pre-prepared solution. Forexample, solutions of baclofen of about 8.0, of about 10.0, or higherthan about 10.0 mg/mL can be readily prepared for immediate use ininstances where the solution is not required to be stable for a periodof more than a few days or weeks.

In further embodiments, stable baclofen solutions of the presentinvention can be provided in a medical package of baclofen solutionsuitable for injection or oral administration. In preferred embodiments,the medical package contains a solution that is compatible withcerebrospinal fluid and therefore suitable for intrathecaladministration. Typically, medical packages suitable for intrathecaladministration will include a sterile, isotonic solution of baclofenfree of pyrogens, antioxidants, preservatives or other potentiallyneurotoxic additives. In related embodiments the medical package willcomprise one or more single dose containers (e.g. ampules) of a sterilebaclofen solution that is suitable for oral or parenteral administrationwith or without dilution prior to administration.

In general, baclofen is introduced to the cerebrospinal fluid by meansof administration by direct injection, administration via an externalintrathecal pump or administration via an internal intrathecal pump,wherein the pump itself is implanted into the abdomen of the patient.The internal pumps are often refilled by means of an injection throughthe skin of the patient into a reservoir in the pump designed to receivethe solution to be administered. The present invention provides medicalpackages suitable for use with any of these routes of administration,including single use or multi-use medical packages for use in directinjection or in the filling or refilling of external or internalintrathecal pumps.

Furthermore, the embodiments of the present invention can be combined toenhance the effectiveness of the methods described above. For example,baclofen solutions can be dissolved in an acidic solution that is heatedor subjected to intense agitation or both, or baclofen solutions can bedissolved in a basic solution that is heated or subjected to intenseagitation or both.

The following examples are included to demonstrate preferred embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques discovered by the inventor to function well in the practiceof the invention, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe invention.

Materials. Baclofen, U.S.P., powder and drug reference standard and 0.9%sodium chloride injection, U.S.P. is obtained from commercial sources.Analytical mobile phase components are HPLC grade and purchasedcommercially. For packaging of the various solutions in syringes, 30-mLBecton-Dickinson syringes are used, fitted with Braun Luer lock “RedCap” syringe tip seals. Becton-Dickinson needles are used to effect thedrug transfers. The syringes, needles, and seals are purchased throughcommercial sources. Similarly, empty sterile 30-mL glass vials arepurchased from a commercial source.

Methods of Sample Preparation. All manipulations are conducted in aClass 100 environment in a biological safety cabinet. Each test solutionis prepared as a pooled sample and then subdivided by (1) drawing 20 mLof the solution into 30-mL Becton-Dickinson syringes having Braun Luerlock “Red Cap” syringe tip seals and (2) sealing the Luer tip with a RedCap Luer tip seal and (3) filling 20 mL of the test solution into 30-mLsterile empty glass vials. Separate sample syringes and sample vials areprepared for each drug concentration at each storage temperature.Separate syringes and vials are prepared for analysis of the drugcontent. Further syringes and vials are used to evaluate the physicalstability of the solutions.

Methods of Sampling and Analysis. Each pooled solution is analyzed andevaluated immediately after preparation. This serves as the initial timepoint evaluation for the test solution. The solution is then packagedinto the syringes and vials as noted under Sample Preparation.

The test solutions in vials and syringes are thoroughly mixed prior tosampling. A 1-mL sample of each test solution from three test syringesand three test vials is collected and chemically analyzed. The samplealiquots are removed from each container after 1, 3, 7, 14, 21, 30 and60 days of storage at 4° C., 23° C., and 37° C. Triplicate HPLCdeterminations are performed at each time point if needed to determinethe maximum stability of baclofen. The contents of the remainingcontainers are visually inspected at each assay time point and 6-mLsamples are collected and fully evaluated for physical stability asindicated under Physical Stability Evaluation above after 1, 3, 7, 14,21, 30 and 60 days.

EXAMPLE 1

Solubilization of Baclofen by Heat and Sonication. Appropriate amountsof baclofen were weighed and added to appropriate volumes of normalsaline in order to produce mixtures containing 4, 5, 6, 8 or 10 mg/mLbaclofen. All samples had undissolved baclofen powder presentimmediately after mixing. Samples having concentrations of 4, 5 or 6mg/mL of baclofen were heated to 70° C. Samples having concentrations of8 and 10 mg/mL of baclofen were heated to 95° C. Intense agitation wasapplied to all of the samples by sonicating the samples during theheating step. Heating and sonication were continued until all of thepowder dissolved, and a clear solution with no residual particulatematter resulted. For the 4, 5, and 6 mg/mL samples, this occurred inabout 20 to 30 minutes. The increased heating and sonication for higherconcentrations resulted in dissolution in about 20 minutes for the 8 and10 mg/mL samples. Again, the solutions were clear with no residualparticulate matter.

After complete dissolution of the samples had occurred, the solutionswere allowed to cool to room temperature and several separate aliquotsof each sample were filtered through 0.22-micron sterilizing filtersinto sterile empty vials. Vials containing samples of each solution werestored under one of three test conditions: vials were stored at roomtemperature or under refrigeration (to simulate normal storageconditions), or at 37° C. (to simulate “in use” conditions in animplanted pump).

EXAMPLE 2

Solubilization of Baclofen by Heat and High-Speed Stirring. Appropriateamounts of baclofen were weighed and added to appropriate volumes ofnormal saline in order to produce mixtures containing 4, 5, 6, 8 or 10mg/mL baclofen. All samples had undissolved baclofen powder presentimmediately after mixing. Samples having concentrations of 4, 5 or 6mg/mL of baclofen were heated to 70° C. Samples having concentrations of8 and 10 mg/mL of baclofen were heated to 95° C. Intense agitation wasapplied to all of the samples by high-speed stirring. A high-speed stirbar was placed in each of the containers for each of the baclofenconcentrations was stirred using a Thermolyne stirrer at a speed ofabout 600 rpm while the solutions were heated. This was designed tosimulate the use of a high-speed high shear mixer in a larger industrialsetting. Again the heating at 70° C. for the 4, 5, and 6 mg/mLconcentrations and to 95° C. for the 8 and 10 mg/mL concentrations andhigh-speed stirring were continued until all of the powder had dissolvedand a clear solution with no residual particulate matter resulted. Thisoccurred within about 20 minutes with all samples.

After complete dissolution of the samples had occurred, the solutionswere allowed to cool to room temperature and several separate aliquotsof each sample were filtered through 0.22-micron sterilizing filtersinto sterile empty vials. Vials containing samples of each solution werestored under one of three test conditions: vials were stored at roomtemperature or under refrigeration (to simulate normal storageconditions), or at 37° C. (to simulate “in use” conditions in animplanted pump).

EXAMPLE 3

Acidification with Back Titration. Baclofen concentrations of 4, 5, 6,8, and 10 mg/mL were prepared by dissolving appropriate amounts ofbaclofen powder in 0.1 N hydrochloric acid. The baclofen powder readilydissolved within a few minutes and a clear solution with no residualparticulate matter resulted. The solutions were then back titrated with0.1 N sodium hydroxide to reach a pH about 5.0 to 5.1, which is withinthe current product pH range for commercial baclofen solutions, andbrought to volume with 0.9% sodium chloride. After complete dissolutionhad occurred, the solutions were filtered through 0.22-micronsterilizing filters into sterile empty vials. The vials were stored atroom temperature, under refrigeration, and at 37° C. to simulate “inuse” conditions in an implanted pump.

EXAMPLE 4

Alkalinization with Back Titration. Baclofen concentrations of 4, 5, 6,8, and 10 mg/mL were prepared by dissolving appropriate amounts ofbaclofen powder in 0.1 N sodium hydroxide. The baclofen powder readilydissolved within a few minutes and a clear solution with no residualparticulate matter resulted. The solutions were then back titrated with0.1 N hydrochloric acid to reach a pH about 6.9 to 7.0, which is withinthe current product range, and brought to volume with 0.9% sodiumchloride. After complete dissolution had occurred, the solutions werefiltered through 0.22-micron sterilizing filters into sterile emptyvials. The vials were stored at room temperature, under refrigeration,and at 37° C. to simulate “in use” conditions in an implanted pump.

EXAMPLE 5

Testing of Solubility Under Various Storage Conditions. Baclofen 4 mg/mLsolutions prepared with heat and sonication (Example 1) as well as the 4mg/mL solutions prepared with heat and high speed stirring (Example 2)have stayed in solution, remaining clear and free of visibleparticulates and unacceptable microparticulates, for over 12 months atroom temperature and for at least one month at 37° C. (the maximumduration tested). Particularly notable is the observation that thesolutions even remained in solution when refrigerated at 4° C. for atleast 60 days (the maximum duration tested).

Baclofen 4 mg/mL solutions prepared by pH adjustment (Examples 3 and 4)and baclofen 5 and 6 mg/mL solutions prepared by all four methods(Examples 1-4) have also remained clear and free of unacceptablemicroparticulates when stored either at room temperature or at 37° C.for at least 60 days. However, when subjected to refrigeration, the 5and 6-mg/mL concentrations developed a precipitate after 14 days and 7days, respectively.

EXAMPLE 6

Physical stability of 8.0 mg/mL baclofen solutions. Most surprisingbecause of the high concentration, the baclofen 8-mg/mL solutionprepared by acidification and back titration to pH 5 (Example 3)remained in solution clear and free of unacceptable microparticulatesfor at least 30 days at room temperature.

EXAMPLE 7

Physical stability of 8.0 mg/mL baclofen solutions. The 8-mg/mL solutionprepared by alkalinization and back titration (Example 4) remains insolution clear and free of unacceptable microparticulates for at least30 days at room temperature.

EXAMPLE 8

Physical stability of 8.0 mg/mL baclofen solutions. The 8-mg/mL solutionprepared by heating and agitation (Examples 1 and 2) remained clear andfree of unacceptable microparticulates for only 14 days at roomtemperature or at 37° C. before developing some trace particulateprecipitation.

EXAMPLE 9

Physical stability of 10.0 mg/mL baclofen solutions. Initially a clearand particle-free baclofen 10-mg/mL solution was prepared using each ofthe methods disclosed in Examples 1 through 4. However, upon standing atroom temperature, crystalline precipitation developed within 1 or 2 daysin all of the 10 mg/mL samples.

EXAMPLE 10

HPLC Analysis to Confirm Baclofen Concentration. A stability-indicatingHPLC analytical method adapted from published methods was used todetermine the concentration of the baclofen samples evaluated in thistesting (Sitaram et al., 1997; Gupta et al., 1998; Johnson C E, et al.,1993; Allen L V, et al., 1996. This method was used to document that atthe higher concentrations the entire amount of baclofen had dissolved,and the solutions were near the target concentrations. All tested samplesolutions were filtered through 0.22-micron filters to remove remainingundissolved drug, if any, prior to analysis. The HPLC analytical methodused is cited in Tables 1 and 2. Analysis of the finished solutiondemonstrated that all of the baclofen had indeed dissolved. Initialbaclofen concentrations for the nominally 4, 5, 6, and 8 mg/mL testsolutions were within 93 to 104% of the target concentrations.

TABLE 1 HPLC Analytical Method Used Baclofen^(a) Column: Symmetry C₁₈, 5μm, 250 × 4.6 mm i.d. Mobile Phase: A. 0.085M ammonium phosphate 78.5%and acetonitrile 21.5% B. Acetonitrile 100% Flow Rate: Gradient. SeeTable 2. Detection: UV 220 nm, 1.0 AUFS Retention Times: Baclofen 4.7min Decomposition products 3.3, 6.4, 17 min ^(a)Precision: Mean ± S.D.(n = 10) 99.8 ± 1.0 μg/mL; percent relative standard deviation was 1.0%.Standard curves range was baclofen 50 to 150 μg/mL. Correlationcoefficients were >0.9999.

TABLE 2 HPLC Mobile Phase Gradient Table Time Flow A B (min) (mL/min)(%) (%) 0 0.8 100 0 5 0.8 100 0 6 1.0 77 23 13 1.0 77 23 15 1.0 100 0 231.0 100 0 25 0.8 100 0

The liquid chromatograph is a Waters LC Module-1 Plus having amultisolvent pump, variable wavelength UV detector, and autosampler inone unit. The system is also controlled and integrated by a personalcomputer running chromatography management software.

EXAMPLE 11

Physical Stability Evaluation. The samples are also evaluated forchanges in turbidity and particulate formation. In addition to visualinspection in normal diffuse fluorescent room light and using ahigh-intensity monodirectional light source (Tyndall beam) against adark background, turbidity is measured using a Hach Company model 2100ANcolor-correcting turbidimeter, and particle sizing/counting is performedusing a light-obscuration particle sizer and counter (HIAC-Royco Model9703 particle sizer/counter).

EXAMPLE 12

Shelf-Life Evaluation. The 4-mg/mL samples prepared with heat andsonication (Example 1) and with heat and high-speed stirring (Example 2)remained in solution for at least one year with no loss of drug at roomtemperature of 23° C. Furthermore, the samples have remained clear andfree of visible particulates and microparticulate precipitation duringthat time period.

EXAMPLE 13

Shelf-Life Evaluation. Baclofen solution at concentrations of 3.0 mg/mL,3.5 mg/mL and 4.0 mg/mL were prepared by heat and sonication as inExample 1 and were stored at room temperature for a period of 24 months.At 24 months, the physical stability of the samples was assessed as inExample 11 and were found to be physically stable by all four methods,that is, all the tested samples were clear and showed an absence ofparticulates. The results of the chemical stability studies are alsogiven in Table 3. The chemical stability of the samples was assessed byHPLC as in Example 10. The percentage of sample remaining in solutionfor each sample is given in Table 3.

Additional baclofen solutions at concentrations of 4.0 mg/mL, 5.0 mg/mL,6.0 mg/mL and 8.0 mg/mL were prepared by heat and sonication as inExample 1 and were stored at room temperature for a period of over 16months. The physical and chemical stability of the samples was assessedat 12 months. As shown in Table 3, at twelve months the 4.0 and 5.0mg/mL solutions remained clear and no particulates were detected by themethods described in Example 11. Visual inspection of the samples atapproximately 16 months showed no change in the solutions. Also as shownin Table 3, at twelve months the 6.0 mg/mL solution was shown to have novisible particulates to the unaided eye, but did contain trace amountsof solid material. These solutions containing trace amounts ofparticulates would generally still be considered pharmaceuticallyacceptable. Visual inspection of this sample at approximately 16 monthsshowed no change in its condition. The 8.0 mg/mL solution remained insolution for at least 30 days, but between day 30 and 60 the baclofenfell out of solution and the sample was not evaluated further.

TABLE 3 Shelf-life Stability of High Concentration Baclofen InjectionStored at Room Temperature Baclofen Physical Chemical Concentration TestPeriod Stability Stability (mg/mL) (months) (yes/no) (% Remaining) 3mg/ml 24 yes  101.7 ± 1.0^(a) 3.5 mg/ml 24 yes  100.0 ± 0.4^(a) 4 mg/ml24 yes   99.5 ± 1.2^(a) 4 mg/ml 12 yes   99.9 ± 0.5  5 mg/ml 12 yes 100.6 ± 0.5  6 mg/ml 12 yes^(b) 102.9 ± 1.0  ^(a)Chemical stabilitytesting did not start until six months after preparation. The 24-monthconcentrations were calculated based on the concentrations measured atsix months. the physical stability was evaluated from study start date.^(b)No visible particulates to the unaided eye. However, a few vialsdeveloped a small amount of trace microparticulates, mostly one or twomicrons in size, after 4 months of storage.

All of the compositions and methods disclosed and claimed herein can bemade and executed without undue experimentation in light of the presentdisclosure. While the compositions and methods of this invention havebeen described in terms of preferred embodiments, it will be apparent tothose of skill in the art that variations can be applied to thecompositions and/or methods and in the steps or in the sequence of stepsof the methods described herein without departing from the concept,spirit and scope of the invention. More specifically, it will beapparent that certain agents that are chemically or physiologicallyrelated can be substituted for the agents described herein while thesame or similar results would be achieved. All such similar substitutesand modifications apparent to those skilled in the art are deemed to bewithin the spirit, scope and concept of the invention as defined by theappended claims.

REFERENCES

The following references, to the extent that they provide exemplaryprocedural or other details supplementary to those set forth herein, arespecifically incorporated herein by reference.

-   -   1. Sitaram B. R., Tsui M., Rawicki H. B., et al., “Stability and        compatibility of intrathecal admixtures containing baclofen and        high concentrations of morphine”, Int. J. Pharm., 1997, 153:        13-24;    -   2. Gupta V D, Parasrampuria J., “Quantitation of        4-(4-chlorophenyl)-2-pyrrolidine in baclofen powder and        tablets,” Drug Develop. Indust. Pharm., 1998, 14: 1623-1628.    -   3. McEvoy G., AHFS Drug Information 2003, Bethesda, Md.:        American Society of Health-System Pharmacists, 2003.    -   4. Ahuja S., “Baclofen,” Analytical Profiles of Drug Substances,        Vol. 14, New York: Academic Press, 1985, pp. 527-548.    -   5. Lioresal Intrathecal package insert, Medtronic Neurological,        Minneapolis, Minn., April, 1997.    -   6. USP Dictionary of USAN and International Drug Names 2003,        Rockville, Md.: United States Pharmacopeial Convention, 2003.    -   7. United States Pharmacopeia 27^(th) ed., Rockville, Md.:        United States Pharmacopeial Convention, 2004.    -   8. Johnson C. E., et al., “Stability of an extemporaneously        compounded baclofen oral liquid”, Am. J. Hosp. Pharm., 1993,        50:2353-55.    -   9. Allen L. V., et al., “Stability of Baclofen, Captopril,        Diltiazem Hydrochloride, Dipyridamole, and Flecainide Acetate is        Extemporaneously Compounded Oral Liquids”, Am J Health-Syst.        Pharm., 1996, 53:2179-2184.    -   10. Cruaud et al., “The Characterization and Release Kinetics        Evaluation of Baclofen Microspheres Designed for Intrathecal        Injection”, Int. J. Pharmacuetics, 177, 1999, 247-257).

1. A stable, aqueous solution comprising baclofen at a concentrationbetween about 3.0 mg/mL and about 4.0 mg/mL.
 2. The solution as recitedin claim 1, comprising baclofen at a concentration of 3.0 mg/mL.
 3. Thesolution as recited in claim 1, comprising baclofen at a concentrationof 3.5 mg/mL.
 4. The solution as recited in claim 1, comprising baclofenat a concentration of 4.0 mg/mL.
 5. The solution of claim 1, whereinsaid composition is stable for at least 12 months at room temperature.6. The solution of claim 1, wherein said composition is stable for atleast 60 days at 37° C.
 7. The solution of claim 1, wherein saidcomposition is stable for at least 24 months at room temperature.
 8. Amethod of managing severe spasticity of spinal cord origin comprisingadministering intrathecally to a patient in need thereof a therapeuticamount of an aqueous solution comprising baclofen at a concentrationbetween about 3.0 mg/mL and about 4.0 mg/mL wherein said solution isstable for at least 30 days at room temperature.
 9. A method of managingsevere spasticity of spinal cord origin comprising administeringintrathecally to a patient in need thereof a therapeutic amount of anaqueous solution comprising baclofen at a concentration of 4.0 mg/mLwherein said solution is stable for at least 30 days at roomtemperature.
 10. A method of managing severe spasticity of spinal cordorigin comprising administering intrathecally to a patient in needthereof a therapeutic amount of an aqueous solution consisting ofbaclofen at a concentration of 4.0 mg/mL wherein said solution is stablefor at least 30 days at room temperature.
 11. A method of managingsevere spasticity of spinal cord origin comprising administeringintrathecally to a patient in need thereof a therapeutic amount of anaqueous solution comprising baclofen at a concentration of 3.0 mg/mLwherein said solution is stable for at least 30 days at roomtemperature.
 12. A method of managing severe spasticity of spinal cordorigin comprising administering intrathecally to a patient in needthereof a therapeutic amount of an aqueous solution consisting ofbaclofen at a concentration of 3.0 mg/mL wherein said solution is stablefor at least 30 days at room temperature.
 13. A method of managingsevere spasticity of spinal cord origin comprising administeringintrathecally to a patient in need thereof a therapeutic amount of asolution consisting of baclofen at a concentration of 4.0 mg/mL innormal saline, wherein said solution is stable for at least 30 days atroom temperature.